A complex immune system protects the mucosal surfaces of the respiratory tract from the constant exposure to pathogenic microorganisms and environmental allergens. The collectin proteins (collagen-like lectins) are components of this multifaceted system. Two of the 6-member collectin family, surfactant protein A (SP-A) and surfactant protein D (SP-D), are present in the lining fluids of the respiratory tract, in good position to provide immunological surveillance against both microbes and allergens. The long-term objectives behind this proposal are to determine the mechanisms of collectin action in pulmonary host defense and the relative importance of the collectins in maintaining human health. To best focus on specific mechanisms a single model organism, influenza virus (IAV), will be studied in several transgenic mouse models of altered collectin expression. The hypothesis to be tested in this proposal is that SP-A and SP-D limit lung injury from IAV infection by distinct and complementary mechanisms, specifically SP-D acts primarily as a direct viral neutralizing molecule blocking infection of the epithelium while SP-a reduces the viral load primarily by enhancing macrophage phagocytosis. The proposal also tests the idea that the collectins present IAV to the cells of the adaptive immune response and modify the cellular and humoral response to infection. These hypotheses will be tested by four specific aims. Aim 1: To determine the respective role of SP-A and SP-D during strain specific IAV infection in vivo. Aim 2: To characterize the effects of SP-A and SP-D on the response of macrophages to IAV. Aim 3: To determine if SP-A or SP-D influences the humoral and cellular immune response to IAV infection. Aim 4: To characterize the critical functional domains of the collectins in mediating the mouse response to influenza virus. Although our studies are focused on a specific organism, we expect the mechanisms underlying collectin-IAV-host interactions will pertain more generally to the action of collectins in respiratory immune responses.